Propofol (chemical name: 2,6-diisopropylphenol) is a sedative-hypnotic agent that has been widely used in clinical practice for induction and maintenance of general anesthesia and for intensive care. Propofol has the characteristics of rapid onset and fast metabolic inactivation, and so it has increasingly been used widely in the world since its first clinical report in 1977. As the water solubility of propofol is only 146 mg/L, its clinical formulation is an oil-in-water (O/W) emulsion, in which propofol accounts for 1%; soybean oil, 10%; glycerol, 2.25%; and purified egg yolk lecithin, 1.2%. In the U.S.A, for example, 0.005% disodium edetate is also included as a bacteria growth inhibitor. This formula is a milk-white liquid with a pH value of 7.0, which is slightly viscous, easily injectable, stable at room temperature, and insensitive to light, and is packed in ampoules, under nitrogen gas. However, this preparation still has many disadvantages. For example, as an emulsion form for injection, various stabilizers and solubilizers contained can inevitably cause allergic reactions. Soybean oil and lecithin contained can breed bacteria easily; therefore, it must be prepared under the strict aseptic condition, and it is hard to store when unsealed. Meanwhile, a big oil droplet contained may cause embolism or even serious cardiac adverse effects. Besides, this kind of formulation cannot overcome the disadvantage of 2,6-diisopropylphenol being easily oxidized and deteriorated. All of these disadvantages have limited the use of 2,6-diisopropylphenol to some extent.
Some chemical methods have been reported to overcome those disadvantages of 2,6-diisopropylphenol, which inevitably involved the preparation of some water-soluble prodrugs by modification of the hydroxyl group of 2,6-diisopropylphenol,such as propofol phosphates disclosed in WO200213810. But some of those compounds could not rapidly release 2,6-diisopropylphenol in vivo and could not achieve a rapid induction of anesthesia. For another example, the prodrugs disclosed in WO2003059255 could release formaldehyde molecules after hydrolysis, which could cause some adverse effects. For one more example, the propofol succinic acid monoester sodium salt disclosed in WO200213810 is a derivative of 2,6-diisopropylphenol with high water-solubility, but it is unstable in aqueous solution, which also limits the development and application of water-soluble prodrugs of 2,6-diisopropylphenol.